U.S. patent number 4,229,838 [Application Number 05/921,680] was granted by the patent office on 1980-10-28 for vascular prosthesis having a composite structure.
This patent grant is currently assigned to Sumitomo Electric Industries, Ltd.. Invention is credited to Hiroshi Mano.
United States Patent |
4,229,838 |
Mano |
October 28, 1980 |
Vascular prosthesis having a composite structure
Abstract
A vascular prosthesis having a composite structure of a porous
tubing of polytetrafluoroethylene with polyethyleneimine in the
pores of the tubing, the polyethyleneimine being
water-insolubilized with the amino groups quaternized and having
heparin ionically bound thereto.
Inventors: |
Mano; Hiroshi (Osaka,
JP) |
Assignee: |
Sumitomo Electric Industries,
Ltd. (Osaka, JP)
|
Family
ID: |
13688390 |
Appl.
No.: |
05/921,680 |
Filed: |
July 3, 1978 |
Foreign Application Priority Data
|
|
|
|
|
Jul 1, 1977 [JP] |
|
|
52/79385 |
|
Current U.S.
Class: |
623/1.43;
427/2.25; 623/1.4; 623/1.49 |
Current CPC
Class: |
A61L
27/16 (20130101); A61L 27/34 (20130101); A61L
33/0029 (20130101); A61L 27/16 (20130101); C08L
27/18 (20130101); A61L 27/34 (20130101); C08L
79/02 (20130101); A61L 27/34 (20130101); C08L
27/18 (20130101); A61L 33/0029 (20130101); C08L
79/02 (20130101) |
Current International
Class: |
A61L
27/00 (20060101); A61L 27/34 (20060101); A61L
27/16 (20060101); A61L 33/00 (20060101); A61F
001/24 () |
Field of
Search: |
;3/1.4,1 ;128/334R
;427/2 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
"A New Vascular Prosthesis for A Small Caliber Artery", by H.
Matsumoto et al., Surgery, vol. 74, No. 4, pp. 519-523, Oct. 1973.
.
"Expanded Polytetrafluoro-Ethylene as a Small Artery Substitute",
by C. D. Campbell et al., Transactions Amer. Society for Artificial
Internal Organs, vol. XX-A, 1974, pp. 86-90..
|
Primary Examiner: Frinks; Ronald L.
Attorney, Agent or Firm: Sughrue, Rothwell, Mion, Zinn and
Macpeak
Claims
What is claimed is:
1. A vascular prosthesis having a composite structure of a porous
tubing of polytetrafluoroethylene with polyethyleneimine in the
pores of the tubing, said polyethyleneimine being
water-insolubilized with the amino groups quaternized and having
heparin ionically bound thereto.
2. The vascular prosthesis of claim 1 wherein the polyethyleneimine
is a microporous polyethyleneimine which is water-insolubilized
with the amino groups quaternized and has heparin ionically bound
thereto.
3. The vascular prosthesis of claim 1 wherein the
polytetrafluoroethylene has a microstructure composed of fibers and
nodes connected to one another by the fibers, and the
microstructure of the outer surface of the tubing differs from the
microstructure of the inner surface of the tubing.
4. The vascular prosthesis of claim 3, wherein the outer surface of
the porous tubing has an average fiber diameter at least two times
larger than the average fiber diameter of the inner surface of the
porous tubing.
5. The vascular prosthesis of claim 3, wherein the direction of the
fiber alignment of the inner surface of the porous tubing is more
radially distributed than the direction of the fiber alignment of
the outer surface of the porous tubing.
6. The vascular prosthesis of claim 3, wherein the long axes of the
nodes at the outer surface of the porous tubing are at least two
times longer than the long axes of the nodes at the inner surface
of the porous tubing.
7. The vascular prosthesis of claim 3, wherein the pore diameter of
the outer surface of the porous tubing is larger than the pore
diameter of the inner surface of the porous tubing.
8. The vascular prosthesis of claim 1, wherein said
polyethyleneimine is present only in those pores of the porous
tubing which are on the inner surface of the porous tubing.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an antithrombic vascular prosthesis
composed of polytetrafluoroethylene and quaternized
polyethyleneimine having heparin bound thereto.
2. Description of the Prior Art
Fabric prostheses composed of a knitted or woven fabric of Dacron
or polytetrafluorethylene in the form of a tube having inner
diameters that are relatively large are now being utilized with
relatively good results. In particular, good results are generally
obtained with vascular prostheses for arteries which have an inner
diameter of at least about 7 mm. Despite this, few small
inner-diameter arteries are clinically acceptable. In venous
applications, small inner-diameter prostheses exhibit a lower
patency rate than in arterial applications. The rate of blood flow
in veins is smaller than in arteries, and to prevent thrombosis, it
is important to inhibit platelet adhesion to the inner surface of
the artificial veins. This requirement is not fully met by
presently available artificial veins.
Some tubings made of stretched or expanded polytetrafluoroethylene
have been demonstrated to be clinically useful as vascular
prostheses for arteries and veins. This is described, for example,
in Soyer et al., "A New Venous Prosthesis", Surgery, Vol. 72, page
864 (1972), Volder et al., "A-V Shunts Created in New Ways", Trans.
Amer. Soc. Artif. Int. Organs, Vol. 19, p. 38 (1973), Matsumoto et
al., "A New Vascular Prosthesis for a Small Caliber Artery",
Surgery, Vol. 74, p. 519 (1973), "Application of Expanded
Polytetrafluoroethylene to Artificial Vessels", Artificial Organs,
Vol. 1, p. 44 (1972), ibid., Vol. 2, p. 262 (1973), and ibid., Vol.
3, p. 337 (1974), Fujiwara et al., "Use of Goretex Grafts for
Replacement of the Superior and Inferior Venae Cavae", The Journal
of Thoracic and Cardiovascular Surgery, Vol. 67, p. 774 (1974), and
Belgian Pat. No. 517,415.
The results of these clinical experiments are summarized below.
When a suitable porous prosthesis is implanted as a conduit within
the arterial system, the fine pores are clogged by clotted blood,
and the inside of the prosthesis is covered with a clotted blood
layer. The clotted blood layer is made up of fibrin, and the
thickness of the fibrin varies, for example, according to the
material of and the surface structure of the prosthesis. Since the
thickness of the fibrin approaches 0.5 to 1 mm when a knitted or
woven fabric of Dacron or polytetrafluoroethylene is used as the
prosthesis, success is achieved only with those blood vessels which
are not occluded due to this increase in wall thickness by the
fibrin layer (that is, arteries having an inside diameter of 5 to 6
mm or more). Generally, knitted or woven prostheses having smaller
inner diameters have not been successful.
A polytetrafluoroethylene tubing which has been stretched has a
microstructure composed of very fine fibers and nodes connected
together by the fibers. The diameters of the fibers vary depending
on various stretching conditions, and can be made much smaller than
fibers of the knitted and woven fabrics mentioned above.
It has been confirmed clinically that when a structure composed of
fibers and nodes is expressed in terms of pore sizes and
porosities, or fiber lengths and nodular sizes, a
polytetrafluoroethylene tubing having a pore size of from about
2.mu. to about 30.mu. (pore sizes below about 2.mu. are
undesirable), a porosity of about 78% to about 92%, a fiber length
of not more than about 34.mu. (fiber lengths of about 40.mu. to
about 110.mu. are undesirable), a nodular size of not more than
about 20.mu., and a wall thickness of about 0.3 mm to about 1 mm
exhibits a high patency rate without substantial occlusion by
fibrin deposition.
It has been reported, however, that venous prostheses exhibit a
much lower patency rate than arterial prostheses, and do not prove
to be entirely satisfactory for prosthetic purposes. It has also
been reported that when a vascular prosthesis has too high a
porosity, a tearing of the prosthesis by the suture used in joining
the prosthesis with the vessel of the patient tends to occur.
In the healing process after implantation, connective tissue first
develops on the outer periphery of the polytetrafluoroethylene
tubing and the tissue organizes, and afterwards the fibrin layer on
the inner surface of the tubing organizes. At this time, a
continuity of the intimas of the host's vessels with the neointima
of the inner surface of the vascular prosthesis is established, and
simultaneously, the fibrin layer is replaced by the fibrous tissue
which has entered the prosthesis through the fine pores from the
periphery of the prosthesis. Furthermore, after a certain period of
time, the neointimas at the inner surface are connected firmly to
the connective tissue lining the outer wall of the prosthesis,
thereby completing the formation of an artery. It is known that
this artery formation requires a period of usually about 4 to 6
months. It is known on the other hand that with vascular prostheses
implanted in veins, the rate of entry of the connective tissue from
the periphery thereof is slower than for arterial implantation.
However, despite these reported clinical results, reproducible,
good results have not been obtained. A porous tubing of
polytetrafluorethylene permits the adsorption of plasma protein.
Platelets adhere to the adsorbed plasma protein to form fibrin
fibers which capture blood corpuscles and become a fibrin deposited
layer. This deposited layer is expected to subsequently form a
pseudointima of the prosthesis. However, the fibrin deposited layer
is frequently too thick, and insufficient nutrition of the
pseudointima or neointima occurs. This will result in disconnection
by necrosis or in thrombic occlusion of the inner surface of the
prosthesis.
SUMMARY OF THE INVENTION
An object of this invention is to provide a vascular prosthesis
having a composite structure composed of a porous tubing of
polytetrafluoroethylene and water-insolubilized and quaternized
polyethyleneimine having heparin ionically bound thereto, with the
polyethyleneimine being provided in the pores of the porous tubing.
Functionally, the surface of the prosthesis is rendered hydrophobic
and is simultaneously charged negatively by the
polytetrafluoroethylene having a low surface energy whereby
antithrombic character is achieved. Polyethyleneimine which is
water-insolubilized and quaternized and has heparin ionically bound
thereto is provided in the pores of the porous tubing of
polytetrafluoroethylene, and consequently, a film of water
molecules strongly bound thereto is formed. This prevents the
adsorption of plasma protein which becomes a trigger for fibrin
deposition. Furthermore, in conjunction with the anticoagulating
action of the heparin, antithrombic characteristics are
achieved.
Another object of this invention is to provide a vascular
prosthesis of a stretched polytetrafluoroethylene tubing in which
the pore size of the outer surface is larger than that of the inner
surface thereby to increase the rate of entry of the connective
tissue from the outer periphery of the prosthesis. The smaller size
of the pores of the inner surface is believed to reduce the surface
stasis of blood flow. Platelet adhesion is reduced by providing
water-insolubilized and quaternized polyethyleneimine having
heparin ionically bound thereto in the pores of the
polytetrafluoroethylene tubing. As a result, the amount of thrombus
formation at the inner surface decreases, and the fibrin layer
becomes extremely thin. Thus, the neointima on the inner surface is
thinner than in a similarly dimensioned prior art vascular
prosthesis.
Still another object of this invention is to provide a vascular
prosthesis of a stretched polytetrafluoroethylene tubing in which
the pore size of the outer surface is larger than that of the inner
surface, thereby allowing the connective tissue from the outer
periphery of the prosthesis to grow and develop fully, and
consequently supplying sufficient nutrient to the neointima formed
at the inner surface to prevent calcification in the prosthesis
wall that may otherwise occur due to degenerative change with the
lapse of time, thus increasing the patency rate of the prosthesis
after implantation.
According to this invention, a microstructure composed of fibers
and nodes which is obtained by stretching a tubing of
polytetrafluoroethylene in at least one axial direction and heating
the stretched tubing to at least about 327.degree. C. is used as
one starting material. Then, the pores of the microstructure are
filed with a solution of polyethyleneimine, and the
polyethyleneimine is subjected to a water-insolubilization
treatment and a quaternization treatment. Then, heparin is
ionically bound to the polyethyleneimine to form a composite
structure. Thus, the invention provides a vascular prosthesis
having a high rate of patency which permits a thin neointima to
form on the inner surface of the prosthesis after implantation with
sufficient nutrition being provided the neointima thereby to retain
the neointima without degenerative change and without occlusion of
the interior cavity of the prosthesis.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
FIG. 1 is a schematic cross-section of a composite structure
vascular prosthesis in accordance with the present invention
wherein 1 represents a porous polytetrafluoroethylene tube having
an outer sidewall 10 and an inner sidewall 11 where pores 12 are
shown filled with polyethyleneimine material 13. Like numerals are
used in FIGS. 2-6 to represent like elements.
FIG. 2 is an embodiment of the present invention similar to FIG. 1
except the composite structure vascular prosthesis has nodes 14
connected to one another by fibers 15, where the microstructure of
outer sidewall 10 and inner sidewall 11 is different.
FIG. 3 is an embodiment of the present invention similar to FIG. 2
except that the diameter of the fibers 15a at the outer sidewall 10
is at least two times the diameter of the fibers 15b at the inner
sidewall 11.
FIG. 4 is an embodiment of the present invention similar to FIG. 2
except that the directions of the fibers 15c at the inner sidewall
11 are distributed more radially than the directions of the fibers
15d at the outer sidewall 10.
FIG. 5 is an embodiment of the present invention similar to FIG. 2
but the long axis of each node 14a at the outer sidewall 10 is at
least two times the long axis of each node 14b at the inner
sidewall 11.
FIG. 6 is an embodiment of the present invention similar to FIG. 2
but the size of the pores 12a at the outer sidewall 10 is larger
than the size of the pores 12b at the inner sidewall 11.
FIG. 7 is an embodiment of the present invention similar to FIG. 1
but polyethyleneimine 13 is present only in the pores 12c at the
inner surface side.
DETAILED DESCRIPTION OF THE INVENTION
In order to stretch and sinter tubings of polytetrafluoroethylene,
the methods described in Japanese Patent Publications No. 13560/67
and U.S. Pat. Nos. 3,953,566 and 3,962,153 can basically be
utilized. First, a liquid lubricant is mixed with a sintered powder
of polytetrafluoroethylene, and the mixture is extruded into a
tubular form by a ram-type extruder. The tubing is stretched at
least monoaxially while the tubing is heated at a temperature of
less than about 327.degree. C., the polytetrafluoroethylene
sintering temperature. Then, while the tubing is fixed so that it
does not shrink, the tubing is heated to a temperature of at least
about 327.degree. C. to set the stretched and expanded structure
and to form a tubing having increased strength.
Any polytetrafluoroethylenes, e.g., homopolymers, which are
commercially available can be used in this invention with those
having a molecular weight ranging from about 1.times.10.sup.6 to
about 9.times.10.sup.7 being preferred.
Polyethyleneimine, another starting material, is used to bind
heparin to the polytetrafluoroethylene tubing to render the tubing
antithrombic and form a hydrophilic film. A suitable molecular
weight range for the polyethyleneimine which can be used in this
invention is about 1.times.10.sup.4 to about 9.times.10.sup.5. Any
commercial grades of polyethyleneimine can be used for this
purpose. Commercially available polyethyleneimines are obtained by
the polymerization of ethyleneimine. Usually, they are not linear
high-molecular-weight polymers, but have a branched structure
containing primary, secondary or tertiary amine groups.
Polyethyleneimine of such a structure suffices for the purposes of
the present invention, and the polyethyleneimine may also contain a
substituent. In short, polyethyleneimines of any structure can be
utilized in the present invention. Since, commercially available
grades can be used, their quality is constant for example in regard
to the degree of polymerization. In actually impregnating or
coating a solution of polyethyleneimine in and on a porous tubing
of polytetrafluoroethylene, the concentration of the
polyethyleneimine and the method of insolubilization are selected
depending on the porosity, pore size, etc. of the porous tubing. In
general, the polyethyleneimine can be employed in a concentration
of above 0.1 to about 30% by weight.
Water is suitable as a solvent for the polyethyleneimine. When the
pore size of the polytetrafluoroethylene tubing is small, the pores
of the polytetrafluoroethylene tubing cannot be directly filled
with an aqueous solution of polyethyleneimine. For this reason, the
tubing is first immersed in a liquid which is soluble in water and
having a low surface tension, such as methanol, ethanol, acetone
and an aqueous solution of a surface active agent, and then in
water to replace the liquid in the pores of the tubing with water.
The tubing is then immersed in an aqueous solution of
polyethyleneimine, preferably at a polyethyleneimine concentration
to about 0.1 to about 20% by weight. Since polyethyleneimine is
also soluble in a lower alcohol such as methanol, ethanol or
ethylene glycol, the polyethyleneimine may be dissolved in such a
solvent and the porous tubing can be impregnated directly with such
a solution.
In order to uniformly impregnate the pores of the porous tubing
with the aqueous solution of polyethyleneimine, a sufficient period
of time for the diffusion of the polyethyleneimine to occur is
allowed to elapse after the immersion before the subsequent
insolubilization reaction step is performed. In general, a
sufficient period of time for the diffusion has been found to be
about 0.1 to about 20 hours. Another method for distributing the
polyethyleneimine uniformly in the pores of the tubing is to repeat
the steps of immersion of the porous tubing in the
polyethyleneimine solution and drying the tubing. It has been
ascertained that by again contacting the porous tubing, which has
been impregnated with the polyethyleneimine solution and then dried
(e.g., at from room temperature (10.degree.-25.degree. C.) to about
100.degree. C., preferably up to 80.degree. C.) with the
polyethyleneimine solution, the solution readily penetrates into
the interior of the pores, and the polyethyleneimine concentration
in the interior spaces of the pores roughly doubles. For repeat
impregnation, drying between impregnations is desirable but not
essential. Vacuum impregnation or pressure impregnation may be
utilized, if desired. In particular, the pores can be effectively
impregnated with the polyethyleneimine solution from the inner
cavity of the porous tubing by applying pressure to the
solution.
In the next step, a chemical reaction to render the
polyethyleneimine water-insoluble is carried out. This chemical
reaction is not particularly critical so long as the
polyethyleneimine is rendered water-insoluble. The type of the
reaction can be chosen freely also in view of the fact that the
material constituting the porous tubing is polytetrafluoroethylene
which has very good chemical resistance and thermal stability.
Polyethyleneimine is a very readily water-soluble polymer.
Water-insolubilization can be achieved by cross-linking the
polyethyleneimine into a network structure. Reaction of the
polyethyleneimine with an aldehyde such as formaldehyde or glyoxal
is a typical example of the crosslinking process. If the reaction
takes place in a single molecule of polyethyleneimine, the linear
molecule changes to a cyclic molecule. If the reaction takes place
between two molecules of polyethyleneimine, the molecules change to
starlike molecules or macrocyclic molecules. When the crosslinking
reaction further proceeds and involves many molecules, a
three-dimensional crosslinked network structure will result. As the
degree of polymerization of polyethyleneimine increases, the
water-insolubilization of the polyethyleneimine can be
advantageously achieved with fewer crosslinking reactions.
Furthermore, the swellability of polyethyleneimine with water
becomes greater. Examples of compounds which react with
polyethyleneimine and act as crosslinking agents include ketones,
carboxylic acids, acid anhydrides, acyl halides, isocyanic acid
esters, isothiocyanic acid esters, and epoxides in addition to the
aldehydes. Reactions with these compounds, with carbonyl group
containing compounds being preferred, can be utilized for
water-insolubilization.
The water-swellability, or the water content, of the
polyethyleneimine after water insolubilization varies greatly
according to the reaction procedure for water insolubilization and
the reaction conditions used. Hence, these factors may be selected
depending or the intended end-use purpose. When a suitable reaction
procedure and suitable reaction conditions are selected, a porous
composite structure can also be obtained which consists of a tubing
of polytetrafluoroethylene and a microporous swollen gel-like
product of polyethyleneimine impregnated in the pores of the
tubing. It is surprising to note that by varying the factors,
described above the pore size of the microporous swollen gel
changes from 10.mu. to 0.01.mu. or even to 0.001.mu.. Thus, the
adsorption of plasma protein can be reduced, and the surface of the
interior cavity of the tubing can be made smooth to an extent that
the stream of the blood flow is not disturbed.
Following the water-insolubilization reaction, a quaternization
reaction is carried out. The water-insolubilized polyethyleneimine
is converted by quaternization into a compound having a quaternary
ammonium salt type cation as a fixed ion. A typical example of a
reaction for this purpose is the reaction of the
water-insolubilized polyethyleneimine with an alkyl halide. Use of
an excess amount of the alkyl halide is preferred in order to
assure complete quaternization. Examples of suitable alkyl halides
which can be used are ethyl chloride, butyl chloride, allyl
chloride, benzyl chloride, ethyl bromide, propyl bromide, butyl
bromide, methyl iodide, and ethyl iodide. A similar reaction can be
carried out by using alkyl sulfates or alkyl sulfonates
corresponding to these halides described above.
The product is then subjected to a treatment to ionically bind
heparin to the fixed cation generated as a result of the
quaternization. Heparin is known to be an anticoagulant for blood.
According to this invention, a vascular prosthesis having
antithrombic properties can be obtained by ionically binding
heparin to the fixed cation. To achieve this, the product is
immersed in an aqueous solution of heparin at room temperature
(e.g., 10.degree.-25.degree. C.) to a temperature of not more than
about 100.degree. C. for 1 hour to several days. A suitable
concentration of heparin which can be employed in this invention is
about 100 to about 10,000 units/ml. The heparin solution may also
be an aqueous solution of a suitable concentration of commercially
available sodium heparin.
Coating or mixing of heparin on or with a material to be used for
medical treatment is also practiced to achieve anti-thrombic
characteristics. However, this method has the defect that heparin
easily comes off from the material. A method involving covalently
bonding heparin to the material is also practiced, but has not
given good anti-thrombic properties. In view of this, ionic bonding
of heparin in accordance with this invention is believed to be most
effective for imparting anti-thrombic properties.
Polyethyleneimine water-insolubilized and quaternized and having
heparin ionically bound threto may be provided only partially in
the pores of the porous polytetrafluoroethylene tubing.
Particularly, in a preferred embodiment, a vascular prosthesis of a
porous polytetrafluoroethylene tubing in which heparin-bound
polyethyleneimine is provided only in those pores which are on the
inner surface of the tubing reduces blood leakage after
implantation, and the interior cavity of the prosthesis is not
occluded because of the antithrombic property of the inner surface
of the tubing. Such a prosthesis exhibits a high patency rate even
in application to small-caliber vessels in which the patency rate
has in the past been regarded as extremely low. In order to provide
water-insolubilized and quaternized polyethyleneimine having
heparin ionically bound thereto in those pores which are on the
inner surface side of the porous tubing, the polyethyleneimine
solution can be impregnated only from the inner surface of the
porous tubing, and the subsequent water-insolubilization reaction
should be started only at the inner surface. The reaction should be
terminated by washing the product with water after an appropriate
period of time before the reaction reaches the outer surface of the
tubing.
In another preferred embodiment of the invention, a
polytetrafluoroethylene tubing whose outer surface and inner
surface have different micro-fibrous structures is used as a
starting material. The micro-fibrous structure comprises fibers and
nodes connected to one another by the fibers. Such a starting
material desirably has a micro-fibrous structure in which the
average fiber size of the outer surface is at least two times the
average fiber size of the inner surface.
Another preferred micro-fibrous structure is one in which the fiber
direction of the inner surface is more radially distributed than
the fiber direction of the outer surface, or the long axes of the
nodes at the outer surface are at least two times longer than those
of the nodes at the inner surface.
In these micro-fibrous structures, the inner surface is finer and
smoother than the outer surface. Consequently, the rate of entry of
the connective tissues from the outer periphery after implantation
increases and the surface stasis of the blood flow on the inner
surface is reduced. Furthermore, platelet adhesion can be reduced
by providing water-insolubilized and quaternized polyethyleneimine
having heparin ionically bound thereto in the pores of the
micro-fibrous structure.
A structure of these types can be obtained by sintering the
stretched tubing at a temperature of at least about 327.degree. C.
while forcibly cooling the inner surface of the tubing and starting
the heating at the outer periphery of the tubing.
The temperature is so adjusted that the resin portion of the inner
surface of the tubing is at a temperature of at least about
327.degree. C., the sintering temperature, while continuously
exposing the inner surface of the tubing to a cooling medium such
as air by continuously introducing the cooling medium into the
interior cavity of the tubing, or continuously reducing the
pressure of the interior cavity of the tubing.
As a result, the resin fibers at the outside surface of the tubing
are exposed for a long time to a temperature of at least about
327.degree. C., and two or more fibers at the outer surface
originally having the same fibrous structure (especially the same
size) as the inner surface coalesce and gradually become thicker.
For example, when the fiber diameter doubles four fibers are fused
and coalesced.
The thickness of the inner surface structural portion of the tubing
and the thickness of the outer surface structural portion of the
tubing are varied by changing the amount of the cooling medium
passed through the interior cavity of the tubing and the amount of
heat supplied externally. When the amount of the cooling medium is
decreased, and the amount of heat supplied externally is increased,
the thickness of the outer surface structural portion increases.
Increasing the amount of the cooling medium results in an increase
in the thickness of the inside surface structural portion. Since in
this case also, the size of the nodular portion does not change,
the nodular dimension of the outer surface is approximately equal
to that of the inner surface.
When the tubing is stretched lengthwise and then expanded in the
radial direction, the micro-fibrous structure of fibers and nodes
changes abruptly. The nodes of a tubing which has been stretched
only in the longitudinal direction have a shape approximating an
ellipsoid and have a relatively uniform size. However, with a
tubing which has been stretched in the longitudinal direction and
then expanded in the radial direction, the nodes generated in the
longitudinal direction divide into smaller portions depending on
the extent of expansion, and fibers form again among the nodes. The
shape of the nodes or the length, direction and size of the fibers
will vary depending on the stretch ratios in the longitudinal
direction and the radial direction. At any rate, it is to be noted
that the shape of the nodes, the length, the size, etc. of the
fibers change depending on the extent of expansion in the radial
direction from the shape, length, size, etc. attained by stretching
the tubing only in the longitudinal direction.
The most preferred embodiment comprises stretching the tubing first
in the longitudinal direction and then expanding the tubing in the
radial direction. By heating the outer surface of the tubing to at
least about 327.degree. C., the crystalline melting point of
polytetrafluoroethylene, but maintaining the inner surface of the
tubing at below 327.degree. C. prior to expansion in the radial
direction, a composite structure can be produced in which the outer
surface of the tubing has a micro-fibrous structure formed by
stretching only in the longitudinal direction and the inner surface
of the tubing has a biaxially stretched micro-fibrous structure
formed by stretching also in the radial direction. Needless to say,
it is possible to change the micro-fibrous structures of the outer
and inner surfaces of the tubing by first expanding the tubing in
the radial direction and then stretching the tubing in the
longitudinal direction.
A more detailed description of the polytetrafluoroethylene tubings
and their characteristics which can be used in this invention
appear in copending applications Ser. No. 760,789, filed Jan. 19,
1977, now abandoned, and Ser. No. 825,513, filed Aug. 17, 1977.
Water-insolubilized and quaternized polyethyleneimine having
heparin ionically bound thereto can be provided in the pores of
such a polytetrafluoroethylene tubing by the procedure described
hereinabove.
The fibrous structure at the outer surface of the tubing is less
dense than that at the inner surface, and this produces various
effects as described below.
Firstly, this serves to increase the mechanical strength of
vascular prostheses made of such a tubing preventing the prosthesis
from being torn in the longitudinal direction by the suture during
implantation. It is possible for only the inner surface fibrous
structure of the tubing to act as a bag-like receptacle for
transporting blood. For application to arteries, however, the
tubing must withstand a blood pressure of about 120 mmHg, and
should not be compressed by elastic fibroblasts that develop on the
outer periphery thereof. In addition, the tubing must withstand
suturing at the time of surgery. The force required to cut the
fibers can be increased by increasing the diameters of the fibers
at the outer surface of the tubing, and increasing the number of
fibers that are aligned at right angles to the direction of
possible tearing. In particular, a tubing that has been stretched
and then expanded to increase the fiber diameter has improved tear
strength.
Secondly, as a result of decreasing the dimension of the fibrous
structure at the inner surface of the vascular prosthesis made of
the polytetrafluoroethylene tubing, the surface resistance of the
tubing blood flow is reduced, and consequently, platelet adhesion
is reduced. Platelets which have contacted the surface of the
prosthesis and adhered thereto aggregate with each other reversibly
in the presence of adenosine diphosphate and calcium ion, after
which they adhere irreversibly and form a thrombus together with
fibrin. The thrombus layer becomes thinner as the amount of
platelets that have adhered decreases. The thickness of the initial
thrombus layer increases as the fibrin deposits onto it, and this
finally causes occlusion. Therefore, in order to obtain vascular
prostheses free from occlusion, it is essential to decrease the
thickness of the initial thrombus layer. This necessity is more
pronounced in veins than in arteries. In other words, a reduction
in the thickness of neointimas on the inner surface of the
prostheses can be expected.
As a third effect, fibroblasts rapidly enter the prosthesis from
the outer periphery of the prosthesis and grow fully as a result of
an increase in the size of the openings in the outer surface
fibrous structure of the prosthesis. It is already known that
fibroblasts readily enter a vascular prosthesis made of a knitted
or woven fabric of Dacron, or polytetrafluoroethylene, etc.,
because such a prosthesis has a tubular wall of a loose structure.
However, bleeding occurs through the wall immediately after
implantation, and results in an increase in the thickness of the
fibrin layer on the inner surface of the prosthesis. Further
increase leads to calcification and occlusion. In a prosthesis made
of polytetrafluoroethylene having the same fibrous structures both
at the outer and inner surfaces, it is essential to decrease the
thickness of the fibrin layer that results from platelet adhesion
by making the pore size sufficiently small to prevent bleeding, and
therefore, the ease of entry of fibroblasts from the outer
periphery of the prosthesis must be sacrificed to some extent.
When the fiber diameter of the outer surface of the prosthesis of
this invention is at least two times larger than the fiber diameter
of the inner surface, it is possible to reduce the thickness of the
fibrin layer at the inner surface of the prothesis and facilitate
entry of fibroblasts from the periphery. Furthermore, nutrient
supply to the neointimas formed at the inner surface of the
prosthesis can be effected sufficiently through capillaries which
densely develop on fully grown fibroblasts. It is possible
therefore to greatly reduce calcification of the neointimas that
may result from nutritional deficiency.
In arterial prostheses, nutrition can be effected not only through
capillaries at the fibroblasts, but also from the blood within the
cavity of the prostheses. However, in venous prostheses, nutrition
from the blood can hardly be expected, and must rely exclusively
upon the capillaries present on the fibroblasts that have come
through the outer periphery. Accordingly, the entry of fibroblasts
from the outer periphery of vascular prostheses is important not
only for the formation of neointimas, but also for preventing
calcification of the neointimas which may occur due to nutritional
deficiency after implantation and thereby for increasing the
patency rate of the prosthesis after operation. This is more
important in venous prostheses.
Vascular prostheses must have pore sizes which are small enough to
keep the blood during circulation from leaking through the tubular
wall, and which are large enough to permit entry of fibroblasts
from the outer periphery without obstruction. With the prosthesis
of this invention, this requirement can be met not only by the
porosity (e.g., of about 78% to about 92%), fiber length (e.g., of
not more than about 34.mu.) and pore size (e.g., of about 2.mu. to
about 30.mu.) of the polytetrafluoroethylene tubing, but also by
the condition of water-insolubilized and quaternized
polyethyleneimine having heparin ionically bound thereto which is
provided in the pores of the tubing.
A polytetrafluoroethylene tubing used as a conventional prosthesis
from which leakage of the circulating blood through the wall of the
prosthesis occurs because of high porosity, etc. can also have
blood leakage prevented by completely filling a microporous swollen
gel of water-insolubilized and quaternized polyethyleneimine having
heparin ionically bound thereto in the pores of the tubing.
Fibroblasts from the outer periphery of the prosthesis can
successively enter the filled polyethyleneimine and thus grow.
The effect of providing the water-insolubilized and quaternized
polyethyleneimine having heparin ionically bound thereto in a
polytetrafluoroethylene tubing having porosity characteristics
within the ranges feasible heretofore as vascular prostheses is
that at the time of contact with the blood, the water of adsorption
of the polyethyleneimine inhibits the adsorption of plasma protein,
and thus it is difficult for a fibrin layer to form. In conjunction
with the anti-clotting action of heparin, this effect provides the
vascular prosthesis with antithrombic properties.
The composite vascular prosthesis of the invention composed of a
porous tubing of polytetrafluoroethylene and water-insolubilized
and quaternized polyethyleneimine having heparin ionically bound
provided in the pores, especially in those pores which are on the
inner surface side, results in little vascular occlusion by the
increased thickness of the fibrin layer after surgical operation
occurring, expedites the healing of the patients, and prevents the
degenerative change of the neointimas formed. Accordingly, the
prostheses in accordance with this invention contribute greatly not
only to surgery but also to industry.
The following Examples are given to illustrate the present
invention more specifically. It should be understood however that
the present invention is not to be construed as being limited by
these examples.
In these examples, the bubble point is the pressure at which the
first air bubble passes through the porous tubing when a pneumatic
pressure is applied to the inner surface of the tubing immersed in
isopropyl alcohol. Unless otherwise indicated herein, all parts,
percents, ratios and the like are by weight.
EXAMPLE 1
A commercially available 30% aqueous solution of polyethyleneimine
(mol. wt.: about 40,000) was diluted with isopropyl alcohol to
prepare a 2% solution. The solution was forced into a porous
polytetrafluoroethylene tubing from the inner surface of the
tubing. The porous tubing had been prepared from
polytetrafluoroethylene by stretching and sintering and had an
inside diameter of 4.3 mm, a thickness of 0.40 mm, a bubble point
of 0.25 kg/cm.sup.2 and a porosity of 80%. The porous tubing was
air dried at 20.degree. C. for 2 minutes, and then immersed for 2
minutes in a 4% aqueous solution of glyoxal to render the
polyethyleneimine water-insoluble. The tubing was washed with
water, dried, and then immersed in a 50% ethanol solution of methyl
iodide at 20.degree. C. for 3 hours to quaternize the
polyethyleneimine. The tubing was washed with water, and heated at
90.degree. C. for 30 minutes in distilled water to remove unreacted
material. Furthermore, the tubing was washed with a 1% aqueous
solution of sodium chloride, dried, and impregnated with an aqueous
solution of heparin sodium in a concentration of 1000 units/ml to
bind the heparin. Two hours later, a part of the tubing was taken
as a sample. The sample was washed with water, and then contacted
with a solution of toluidine blue indicator, whereupon it assumed a
reddish violet color. Thus, the bonding of heparin was confirmed.
The resulting tubing had a bubble point of 0.29 kg/cm.sup.2.
EXAMPLE 2
A commercially available 30% aqueous solution of polyethyleneimine
(mol. wt.: about 50,000) was diluted with isopropyl alcohol to
prepare a 7% solution. The solution was forced into the same type
of porous polytetrafluoroethylene tubing as described in Example 1
from the inner surface of the tubing, dried in air at 20.degree. C.
for 2 minutes, and immersed for 2 l minutes in a 5% aqueous
solution of glyoxal to render the polyethyleneimine
water-insoluble. In the same manner as in Example 1, the tubing was
subjected to a quaternization reaction and a heparin-binding
treatment. The bonding of heparin was confirmed in the same manner
as in Example 1. The resulting tubing had a bubble point of 0.44
kg/cm.sup.2.
While the invention has been described in detail and with reference
to specific embodiments thereof, it will be apparent to one skilled
in the art that various changes and modifications can be made
therein without departing from the spirit and scope thereof.
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